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Research Article |

Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy

The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.

GanDouLing, Wilson Disease-Associated Liver Fibrosis, Autophagy, PI3K/AKT/mTOR Pathway

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, et al. (2023). Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. American Journal of Clinical and Experimental Medicine, 11(4), 73-85.

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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